There is abundant evidence linking brain monoamine neurotransmitter systems to behaviors such as alcoholism, aggression, and reward, and psychiatric states including depression and schizophrenia. The evidence consists of correlations between monoamine levels and psychiatric disease and behavior in humans, and drug effects in humans and experimental animals. The next step is to link specific molecules with behavioral effects. One approach to this issue is to use viral vectors to deliver constructs that will modulate the level of specific behaviorally relevant proteins in vivo. The approach is now used routinely to deliver therapeutic molecules to the brain. We are using neurotropic viral vectors to manipulate levels of endogenous molecules involved in monoamine neurotransmission (e.g. tyrosine hydroxylase, tryptophan hydroxylase, monoamine transporters). This is done by antisense constructs to reduce levels of specific molecules, or by using constructs which will overexpress specific molecules. This approach will allow us to produce brain region specific, reversible changes (either increases or decreases) in the level of specific molecules of interest, and study the effects of such manipulations on alcohol intake and behavior. We have constructed amplicon vectors which express sense or antisense RNA to tyrosine hydroxylase and the serotonin transporter, under the control of the herpes virus a 4 promoter. The bicistronic viral particles also express the Lac Z gene under the control of the a 22 promoter. This will allow us to identify and quantitate the number of infected cells following injection into the rat brain (by staining for Lac Z), and thereby "normalize" behavioral effects to the number of infected target cells. Viral vectors have been generated and qualified for effective gene delivery in (NGF treated PC12) cells in culture. Viruses are being injected into brain regions (raphe nuclei, locus coeruleus, ventral tegemental area) in adult rats to assess the role of specific gene products in alcohol intake, other behavioral measures, and animal models of psychiatric disease.